Klebsiella pneumoniae is a gram-negative, facultative anaerobic, rod-shaped bacterium colonizing mostly of the respiratory and urinary tracts and causing K. pneumoniae infections (KPIs). KPI is the main cause of nosocomial infections, primarily affecting immunocompromised patients. In the last ten years, infections caused by K. pneumoniae are becoming an important challenge in health-care settings due to the emergence of strains resistant to almost all available antimicrobial agents and their worldwide dissemination. Infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) are responsible of high rates of morbidity and mortality. Thus, prevention of infections caused by CRKP is highly desirable, and vaccination of risk groups is the most cost-efficient and the most powerful means for avoiding future outbreaks of CRKP. Although, during the last 40 years, many attempts aiming at developing effective vaccines against K. pneumoniae were reported, up to present, there is no vaccine available for prophylactic or therapeutic use against carbapenem-resistant Klebsiella pneumoniae infections.
Like most bacteria, K. pneumoniae usually develop capsules composed of complex polysaccharides on the bacterial surface, which are highly immunogenic and nontoxic. In comparison with proteins, carbohydrates are evolutionarily more stable and have been exploited in a series of commonly employed vaccines. When covalently connected to a carrier protein, oligosaccharide antigens can elicit long lasting, T-cell-dependent protection.
The repeating unit of the capsular polysaccharide of carbapenem-resistant K. pneumoniae strains responsible of the outbreaks occurring in 2011 was elucidated (Carbohydr. Res. 2013, 369, 6-9) and consists of α-L-Rha-(1→4)-[β-D-Gal-(1→3)]-α-D-GalA-(1→2)-α-L-Rha-(1→2)-α-L-Rha-(1→2)-α-L-Rha (see FIG. 1).
The structure of the capsular repeating of Klebsiella K19 was also elucidated (Carbohydr. Res. 1986, 157, 13) and consists of a hexasaccharide repeating unit, which structurally differs from the saccharides claimed herein.

Repeating unit of capsular polysaccharide from Klebsiella pneumoniae K19
The capsular polysaccharide from Klebsiella pneumoniae K19, the capsular polysaccharide from Klebsiella pneumoniae K19 without the branching α-L-Rhap and the disaccharide αGlc1→3Gal-OH obtained via partial hydrolysis of said capsular polysaccharide were isolated. However, the isolated structures differ significantly from the saccharides claimed in the present patent application.
WO 9830224 A1 provides a composition for inhibiting IgE antibody production and response in vivo comprising a capsule component of a Klebsiella oxytoca and
Klebsiella pneumoniae, or a fragment thereof produced by treatment of said capsule with an acid, a base or a reducing agent. Besides the fact that Klebsiella oxytoca and Klebsiella pneumoniae strain 19 have a capsular polysaccharide repeating unit which structurally differs from the saccharides provided in the present patent application, the isolated polysaccharides of WO 9830224 A1 are in fact mixtures of several polysaccharides having an average molecular weight superior to 1×105 i.e. significantly higher than the saccharides of the present invention.
EP 0735049 A2 provides a process for producing a polysaccharide having the following repeating unit:
from polysaccharide-productive Klebsiella oxytoca TNM-3. The disclosed heteropolysaccharide having a molecular weight of 1000 to 10000000 is used as humectant, antistatic agent, film-forming agent or dispersant. The repeating unit of the polysaccharide disclosed by EP 0735049 A2 differs from the saccharidic structure of the compounds claimed in the present invention by the presence of an α-D-Glc residue instead of an α-L-Rha residue. Additionally, the isolated polysaccharides of EP 0735049 A2 are in fact mixtures of several polysaccharides having an average molecular weight of about 106.
It is the objective of the present invention to provide a well-defined synthetic saccharide of general formula (I) that is related to carbapenem-resistant Klebsiella pneumoniae capsular polysaccharide and contains a protective immunogenic glycan epitope i.e. a glycan epitope that elicits antibodies which protect against diseases caused by carbapenem-resistant Klebsiella pneumoniae. Said saccharide can be conjugated to an immunogenic carrier to provide a conjugate and pharmaceutical composition thereof that are useful for prevention and/or treatment of diseases associated with carbapenem-resistant Klebsiella pneumoniae. Furthermore, the synthetic saccharide of general formula (I) is useful as marker in immunological assays for detection of antibodies against carbapenem-resistant Klebsiella pneumoniae bacteria.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.